review article...

Hindawi Publishing CorporationInternational Journal of Alzheimer’s DiseaseVolume 2012, Article ID 314185, 11 pagesdoi:10.1155/2012/314185

Review Article

Microglia in Alzheimer Disease: It’s All About Context

Tara M. Weitz1 and Terrence Town1, 2, 3

1 Regenerative Medicine Institute Neural Program and Department of Biomedical Sciences, Cedars-Sinai Medical Center,8700 Beverly Boulevard, Steven Spielberg Building Room 345, Los Angeles, CA 90048, USA

2 Department of Neurosurgery, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Steven Spielberg Building Room 345,Los Angeles, CA 90048, USA

3 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA

Correspondence should be addressed to Terrence Town, [email protected]

Received 13 February 2012; Accepted 9 April 2012

Academic Editor: Colin Combs

Copyright © 2012 T. M. Weitz and T. Town. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Neuroinflammation is now regarded as both an early event and prime mover in the pathobiology of Alzheimer disease (AD), aneurodegenerative disease that represents a growing public health threat. As the resident innate immune cells within the centralnervous system, microglia are centrally positioned as key orchestrators of brain inflammation. It is now accepted that numerousforms of activated microglia exist. Furthermore, while some types of reactive microglia are detrimental, others can actually bebeneficial. In the context of AD etiopathology, much debate surrounds whether these enigmatic cells play “good” or “bad” roles.In this article, we distill a complex clinical and experimental literature focused on the contribution of microglia to AD pathologyand progression. A synthesis of the literature only seems possible when considering context– the conditions under which microgliaencounter and mount immunological responses to AD pathology. In order to carry out these diverse contextual responses, anumber of key receptors and signaling pathways are variously activated. It will be critically important for future studies to addressmolecular mediators that lead to beneficial microglial responses and therefore represent important therapeutic targets for AD.

1. Introduction

More than twenty years ago, groundbreaking studies by Wis-niewski and his colleagues sparked debate over the relation-ship between microglia and β-amyloid plaques in Alzheimerdisease (AD). In their electron microscopic observations ofmicroglia associated with β-amyloid deposits in the brainparenchyma and cortical vessel walls of AD patients’ brains,Wisniewski and his colleagues discovered that ∼80% ofa morphologic structure they termed the “amyloid star”was covered by microglia [1, 2]. Although they found thatmicroglia had the ability to phagocytose Aβ in vitro, theseinnate immune cells appeared in close proximity to amyloidplaques in brains of AD patients but did not contain β-amyloid fibrils in their lysosomal compartments. Theseultrastructural observations led Frackowiak and coworkersto hypothesize that microglia were unable to phagocytoseand remove Aβ in vivo and were instead responsiblefor the manufacture of amyloid fibers [3]. In contrast,

Wisniewski did observe β-amyloid fibrils in the lysosomesof macrophages that had infiltrated the brain from theperiphery in AD patients with rare comorbid stroke [4]—findings that were later confirmed by Akiyama and McGeer[5].

Rooted in these initial landmark studies of Wisniewski,it is now recognized that there are at least two classes ofphagocytic cells responsible for the innate immune responsesin the brain—the endogenous microglia and the exogenoushematogenous macrophages [6–8]. Microglia are the brain-resident macrophages derived from monocyte precursorsduring embryogenesis and provide the initial response toinjury from within the central nervous system (CNS).Activation of microglia via neural insults leads to thesynthesis of an array of proinflammatory mediators, whichcan be beneficial for clearing infections and for tissue repair;but, if left uncontrolled, this response can go unresolvedand perpetrate bystander neural insult. Thus, in addition totheir role as the first responders to CNS injury, activated

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microglia (and astrocytes) can participate in a form ofchronic neuroinflammation termed “reactive gliosis,” whichhas been implicated in the pathoetiology of a myriad ofneurodegenerative diseases. The second class of phagocyte,peripherally-derived macrophages, arises from bone marrowprecursors and will be referred to in this review as hematoge-nous macrophages. These cells can be recruited to the CNSin health and after CNS injury and are primarily believedto traverse the blood-brain barrier (BBB) at postcapillaryvenules [9]. While hematogenous macrophages typicallyremain in the perivascular space, they can be recruitedinto the brain parenchyma by chemokines and cytokines.These proteins are typically released following activation ofmicroglia and astrocytes upon CNS insult and can causeblood-borne mononuclear cells to differentiate into cellsthat closely resemble brain-resident microglia. Finally, recentfocus has been directed towards a third class of brainphagocyte known as the perivascular macrophage. Thesecells have been found to play an important role in remodelingcerebrovascular Aβ deposits in a transgenic mouse model ofcerebral amyloidosis [10].

Even though the pioneering observations of Wisniewskiand his colleagues were made more than two decades ago,it is only recently and with the availability of moderncellular and molecular biology techniques that the rolesof brain phagocytes have been more fully interrogated inAD. Still, their significance in the pathoetiology and—evenmore intriguingly—as a possible treatment modality for AD,remains unclear. What is clear from the studies of the pasttwenty years, however, is that resident local and peripherally-infiltrating brain macrophages play complex roles in thepathobiology of AD.

2. “Bad” versus “Good” Microgliain Alzheimer Disease

It has previously been suggested that microglial activation isnot simply a single phenotype, and that a continuum existswith antigen presenting cell function (adaptive activation)at one pole and phagocytic cell function (innate activation)at the other [11]. Accordingly, expression profile studiesof macrophages in AD and in mouse models of cerebralamyloid also suggest that there is functional heterogeneityin the activation states of microglia that may contribute todisease outcome [12–14]. These innovative concepts supportthe notion that the context of microglial activation is a keyfactor in determining what role (whether “bad” or “good”)these enigmatic cells play in AD.

3. A Case for “Bad” Microglia

3.1. Evidence from Patients. The concept that microglia pri-marily play a detrimental role in AD is supported by theWisniewski studies and by early epidemiologic findings. Ingeneral, results from these studies are interpreted as lendingsupport to the idea that activated microglia are likely moreharmful than helpful to an AD-afflicted brain. For instance,activated microglia secrete the proinflammatory innate

cytokines including tumor necrosis factor-alpha (TNF-α)and interleukin-1beta (IL-1β), which can directly injureneurons at superphysiologic levels [15, 16].

In addition to the well-accepted notion that microgliaare closely associated with senile plaques in AD, it has alsobeen shown that numerous inflammatory mediators are up-regulated in affected areas of the AD brain [17]. Theseobservations have led to the hypothesis that individualsbeing treated on a long-term basis with anti-inflammatorymedications might be afforded prophylaxis against chronicneuroinflammation and may therefore be at reduced riskfor developing AD. In accord with this concept, a numberof epidemiologic studies in the early 1990s found thatincidence of dementia in elderly patients with arthritiswas lower compared to the general population [18–20].In addition, evidence from neuropathologic studies sup-ports the notion that nonsteroidal anti-inflammatory drugs(NSAIDs; often prescribed for arthritis) reduce microglialactivation and thereby dampen brain inflammation [21].Specifically, Mackenzie and Munoz compared brains fromelderly, nondemented arthritic patients with a history ofchronic NSAID use and nondemented control subjects thatwere not NSAID users and found that this latter grouphad (on average) three-fold more activated microglia thanthe former. However, interpreting these results is not sostraightforward, as arthritis was used as a surrogate forNSAID use in many of these early studies, raising a possible“confounding by indication” issue. Further, The Goldegroup has shown that a subset of NSAIDs lower Aβ1−42,widely considered the neurotoxic Aβ species, independentlyof cyclooxygenase (COX) activity [22]. Nonetheless, theseinitial reports prompted more recent work that focusedmore specifically on NSAID use, and there are now over25 epidemiologic studies that have shown an inverse riskrelationship between NSAID use and AD. A systematicreview of these studies uncovered an approximate 50%reduced risk of AD enjoyed by NSAID users compared tononusers [23].

3.2. Evidence from Mouse Models. The effects of NSAIDshave also been evaluated in transgenic mouse models ofcerebral amyloidosis. In the earliest study, Lim et al. testedthe effects of 6-month-long treatment of Tg2576 mice withibuprofen, beginning at 10 months of age when Aβ plaquesfirst appear in these mice. They found that treated animalshad significantly reduced amyloid deposition as well asblunted expression of the reactive astrocyte marker glialfibrillary acidic protein (GFAP) and the proinflammatorycytokine, IL-1β [24]. Other groups confirmed the ibuprofenresults in Tg2576 mice, amyloid precursor protein (APP)plus presenilin-1 (PS1) double transgenics (termed APP/PS1mice) and APPV717I transgenic mice, all of which showedreduced microglial activation and fewer amyloid depositsfollowing treatment [25–27]. Heneka and colleagues alsotested the effects of curcumin, a naturally-occurring NSAIDderived from turmeric, which is considered to be a lesstoxic alternative to COX-2 inhibitors like ibuprofen. Theyfound decreased IL-1β and GFAP levels as well as attenuated

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plaque burden in treated mice [27]. Furthermore, treatmentof PS1/APP doubly transgenic mice with the nitric oxide-donating NSAID NCX-2216 reduced amyloid load via amechanism thought to involve phagocytic microglia [25, 28].These studies demonstrate that early treatment with NSAIDscan reduce neuroinflammation and amyloid plaque burdenin three different transgenic mouse models of cerebralamyloid deposition. However, it should be noted that studiesdone with the selective COX-2 inhibitor celecoxib failedto reduce inflammatory burden and, in one study, actuallyincreased abundance of Aβ1−42 peptide in transgenic ADmodel mice [25, 29]. Therefore, it seems that certain NSAIDsare capable of reducing microgliosis and amyloidosis inseveral different transgenic mouse models, while othersare not as effective or even produce converse results. Thissuggests that microglia likely have different responses to suchtreatment depending on the mechanism of action of thecompound and/or the nature of the inflammatory milieu atthe initiation of, or even during the course of treatment.

Studies using mouse genetics as a powerful tool toelucidate the role of microglia in AD pathogenesis havealso helped to establish the existence of “bad” microgliathat promote disease progression. In early studies doneby our group, Aβ-stimulated microglia treated with CD40ligand (CD40L) showed increased TNF-α production andpromoted injury of primary cortical neurons. In addition,these studies demonstrated that microglia from transgenic“Swedish” mutant APP (Tg2576) mice deficient for CD40Lexhibited reduced activation compared to microglia fromCD40L-sufficient transgenic Tg2576 littermates [16]. More-over, a separate study showed that genetic ablation ofCD40L in APP/PS1 mice reduced amyloid plaques andmitigated astrocytosis and microgliosis [30]. Further in vitroinvestigations showed that CD40-CD40L interaction led todecreased microglial phagocytosis of exogenous Aβ1−42 andincreased production of proinflammatory cytokines. CD40ligation in the presence of Aβ1−42 led to “adaptive” activationof microglia, as evidenced by increased colocalization ofmajor histocompatibility complex class II (MHC II) withAβ. In addition, when cultured microglia were exposedto Aβ1−42 in the presence of CD40L and cocultured withCD4+ T cells, T cell-derived interferon-gamma (IFN-γ)and interleukin-2 production were stimulated, suggestingthat CD40 signaling promotes a microglial proinflammatoryantigen presenting phenotype [31]. In the context of CD40-CD40L interaction, these results collectively suggest thatmicroglia become proinflammatory and play a primarilydeleterious role in progression of AD-like pathology.

Additional early evidence for detrimental effects of ac-tivated microglia in AD came from Qiao and colleagues.Those authors chronically administered the bacterial endo-toxin lipopolysaccharide (LPS) intracerebroventricularly toAPPV717F mice that either expressed apolipoprotein E(apoE+/+) or were apoE deficient (apoE−/−) [32]. While allLPS-treated mice exhibited global astrocytosis and amyloidplaque-localized microglial activation, Qiao et al. foundsignificant acceleration of amyloid deposition in LPS-treatedcompared to vehicle-treated APPV717F-apoE+/+ mice, whilethis effect was not observed in APPV717F-apoE−/− mice.

These experiments suggest that experimental induction ofmicroglial activation by chronic administration of LPS canaccelerate amyloidosis in a transgenic mouse model of ADin the presence of apoE, and support the idea that activatedmicroglia exacerbate cerebral amyloidosis.

More recent studies by Mori and colleagues showedthat overexpression of the proinflammatory cytokine-likemolecule human S100B (huS100B) in the Tg2576 mousemodel of cerebral amyloid deposition resulted in increasedparenchymal and cerebrovascular β-amyloid deposits andelevated Aβ levels [33]. These effects were accompanied byincreased amyloidogenic processing of APP in addition toreactive astrocytosis and microgliosis in Tg2576-huS100Bmice. The results by Mori et al. lend further support to thenotion that some forms of glial activation (brought aboutin this case by reactive astrocyte-derived S100B) exacerbateAD-like pathology and are thus likely detrimental to the AD-afflicted brain.

In addition to proinflammatory cytokines, chemokinesplay critical roles in orchestrating movement (chemotaxis)of microglia toward noxious stimuli including β-amyloiddeposits. Recent studies by Fuhrmann and colleagues haveshown that knocking out the expression of the fractalkinereceptor, Cx3cr1, can prevent neurodegeneration [34]. Theexpression of Cx3cr1 is exquisitely restricted within theCNS to microglia and is considered to be a critical factorin neuron-microglia communication. Fuhrmann and col-leagues used intravital two-photon imaging to observe inter-actions between microglia and neighboring neurons in 3xTg-AD mice, which overexpress pathogenic mutant forms ofPS1 (M146V), “Swedish” mutant APP, and tau (P301L) [35].These 3x Tg-AD mice were crossed with a transgenic mouseline expressing yellow fluorescent protein in cortical layers IIIand V and another line expressing green fluorescent proteinin place of the endogenous murine Cx3cr1 locus. Time-lapseintravital imaging showed neuron loss in Cx3cr1-sufficientmice while neurons in Cx3cr1-deficient mice survived. Inaddition, they observed that Cx3cr1-sufficient microgliarapidly mobilized toward neurons destined for degeneration.However, Cx3cr1-deficient mice did not exhibit changein Aβ abundance, suggesting that the phagocytic abilityof microglia in these mice was either not altered or notinvolved in the observed neuron loss phenotype. Similarstudies by Bruce Lamb, Richard Ransohoff, and their col-leagues have shown that Cx3cr1 deficiency results in a genedose-dependent reduction in β-amyloid deposition in twodifferent mouse models of AD: APP/PS1 and R1.40 [36].Interestingly, in their models, Cx3cr1 deficiency also resultedin reduced numbers of microglia surrounding Aβ depositsas well as attenuated immunostaining for CD68 (but notCD45) and altered expression of inflammatory cytokines andchemokines, including reduced levels of TNF-α and CCL2mRNAs, but elevated IL-1β mRNA levels. Moreover, theauthors demonstrated in vivo and in vitro that Cx3cr1−/−

microglia had enhanced ability to phagocytose Aβ. While thestudy by Fuhrmann and coworkers did not show differencesin Aβ abundance between Cx3cr1-sufficient and -deficientmice, Lee et al. suggested that Aβ aggregates in 3x Tg-ADmice may be more intracellular than extracellular at the age


Table 1: “Bad” microglia in Alzheimer disease.

Publication(s) Type of Study Observations

Wisniewski et al., 1989 [1], 1992[2]; Frackowiak et al., 1992 [3]

NeuropathologicMicroglia are “frustrated phagocytes” responsible formanufacture of amyloid fibrils and not for their removal.

Meda et al., 1995 [15] In vitroActivated microglia secrete proinflammatory cytokines thatpromote neural injury at high levels.

Tan et al., 1999 [16] Mouse models

Aβ and CD40L-stimulated microglia release TNF-α thatinjures primary cortical neurons. CD40 ligand-deficientTg2576 mice have reduced microglial activation and tauhyperphosphorylation.

McGeer et al. 1990 [18], 1992 [19],1996 [20]

EpidemiologicThere is lower incidence of dementia in elderly patients witharthritis compared to the general population.

Mackenzie and Munoz, 1998 [21] NeuropathologicChronic NSAID users with senile plaques have 3-fold lessactivated microglia than non-users.

Szekely et al., 2004 [23] EpidemiologicSystematic review of over 25 epidemiologic studies shows∼50% reduced risk of AD associated with NSAID use.

Lim et al., 2000 [24], 2001 [72] Mouse modelsNSAID-treated Tg2576 mice have significantly reducedamyloid deposition, astrogliosis, and IL-1β abundance.

Jantzen et al., 2002 [25]; Yan et al.,2003 [26]; Heneka et al., 2005 [27]

Mouse modelsIbuprofen-treated Tg2576, APP/PS1 or APPV717I transgenicmice have reduced microglial activation and amyloiddeposits.

Tan et al., 2002 [30] Mouse modelsGenetic or pharmacologic ablation of CD40 ligand in Tg2576mice reduces cerebral amyloidosis and mitigates gliosis.

Townsend et al., 2005 [31] In vitroCD40 ligand in the presence of Aβ1–42 promotes a microglialproinflammatory antigen presenting cell phenotype.

Qiao et al., 2001 [32] Mouse modelsChronic intracerebroventricular injection of LPS acceleratesAβ plaque load in APPV717F transgenic mice.

Mori et al., 2010 [33] Mouse modelsForcing expression of proinflammatory S100B acceleratesglial activation and cerebral amyloid pathology in Tg2576mice.

Fuhrmann et al., 2010 [34] Mouse modelsCx3cr1 endorses microglial-mediated neuronal loss in 3xTgAD mice.

Lee et al., 2010 [36] Mouse modelsCx3cr1 deficiency reduces cerebral amyloid and reactivemicroglia in APP/PS1 and R1.40 mice. Cx3cr1−/− microgliahave greater Aβ uptake.

Sundaram et al., 2012 [38] Mouse models

Neuroinflammation occurs early and promotesneurodegeneration mediated by lysophosphatidylcholine andCdk5/p25. Inducible p25 expression in vivo triggersneuroinflammation and intraneuronal Aβ.

at which this study was done, therefore affecting the abilityof microglia to phagocytose these deposits. Nonetheless,these studies suggest that Cx3cr1 signaling plays a role in(a) homing of microglia to neurons that are destined fordeath and (b) determining microglial responses to cerebralamyloidosis. In both cases, signaling through Cx3cr1 seemsto direct microglia to respond in such a way that aids ratherthan combats the progression of AD-like pathology.

Finally, previous studies, chiefly from the group ofLi-Huei Tsai, have established that activation of cyclin-dependent kinase five (Cdk5) via proteolytic cleavage ofp35 to p25 is a key event in AD patient brains that canpromote neurodegeneration [37]. However, the role of braininflammation in this process was not previously clear. Ina very recent study, the Kesavapany group examined theconsequences of driving p25/Cdk5 activity both in vivo and

in vitro on neuroinflammation and neuronal death [38].The authors demonstrated that the Cdk5/p25 pathway trig-gered neuroinflammation via lysophosphatidylcholine thatproceeded and led to neurodegeneration and neuronal lossin vitro. In addition, they showed that inducible Cdk5/p25expression in vivo caused early neuroinflammation followedby later accumulation of copious intraneuronal Aβ. Oneinterpretation of this finding is that Aβ production signifiesan acute-phase stress response that can both be initiated byneuroinflammation and drive it. If this is true, then one couldimagine a feed-forward loop endorsing a constellation ofdamaging inflammatory mediators. These findings providedirect evidence that neuroinflammation, at least as initiatedby Cdk5/p25 activation, occurs early and can promoteneurodegenerative changes. All of these studies suggestingdetrimental actions of microglia are summarized in Table 1.


4. A Case for “Good” Microglia

4.1. Evidence from Humans and Preclinical Mouse Models.Inflammatory responses are not always deleterious, and areoften even necessary for survival. Given the exquisite sensi-tivity of neurons to inflammation-induced bystander injuryhowever, there is a fine line between neuroinflammationthat results in tissue repair versus excessive damage to braincells [39]. Epidemiological findings demonstrating reducedrisk for AD in patients using NSAIDs led to the designof the Alzheimer disease anti-inflammatory prevention trial(ADAPT), a randomized controlled trial to test the asso-ciation of NSAID use with cognitive function over timein nondemented elderly individuals. The result of this trialindicated no protection afforded by NSAIDs (naproxen orcelecoxib) on cognitive scores, and weak evidence for lowercognitive scores in naproxen users [40, 41]. This latter resultsuggests that chronic use of naproxen might have actuallybeen detrimental in the ADAPT study. If correct, there existsa possibility that microglial activation was actually beneficialand that treatment with naproxen could have negated thiseffect. While these results need to be interpreted withcaution since the trial was prematurely halted due to fearof cardiotoxicity associated with certain NSAIDs, other trialstesting NSAIDs for treatment of AD or as preventative agentsfor mild cognitive impairment also had null findings [42].That the clinical studies did not support epidemiologicalfindings raises the possibility that the context of microglialactivation and other factors such as whether individualswere cognitively healthy or “on the verge” of conversion tomild cognitive impairment or to AD at the time of NSAIDtreatment are critically important outcome determinants[43]. Also, because many of the healthy elderly participants inthe ADAPT trial were arthritics, these individuals’ peripheralimmune environment may impact their risk for later devel-oping AD [44] and therefore could represent a confound tointerpreting the risk relationship between NSAID use anddevelopment of AD.

While the above reports investigated the effects ofNSAIDs in the clinic, studies in the late 1990s from DaleSchenk and colleagues at Elan pharmaceuticals yieldedsurprising results in preclinical mouse models. They admin-istered peripheral injections of Aβ1−42 plus complete Fre-und’s adjuvant into young PDAPP transgenic mice, whichoverexpress mutant APP. Their intention was to worsen AD-like pathology in these mice. However, they instead foundthat Aβ1−42 plus adjuvant given to young mice essentiallyblocked β-amyloid plaque formation, and treatment of olderanimals significantly mitigated the extent of cerebral amyloiddeposits. In addition, Schenk and colleagues observed MHCII-positive microglia colocalized with Aβ plaques in Aβ1−42

treated mice, which were not observed in control micetreated with PBS plus adjuvant [45]. These results were sup-ported by independent studies that demonstrated decreasedbehavioral impairment in Aβ-immunized PDAPP mice [46,47]. In a subsequent study, Bard and colleagues showed thatpassive transfer of Aβ antibodies from vaccinated mice totransgenic PDAPP mice also reduced cerebral amyloidosis.In that study, they observed punctate immunoreactivity for

Aβ that co-localized with activated microglia, and suggestedthat Aβ plaque clearance was mediated by antibodies againstamyloid β-peptide that crossed the BBB and triggeredmicroglial cells through Fc receptor-mediated phagocytosis[48]. While microglia are generally regarded as inefficientAβ phagocytes [11], Bard and colleagues suggested thepassive Aβ vaccine was somehow able to lure microglia intophagocytosing Aβ antibody-opsonized plaques.

Based on encouraging results in mouse models, Elanpharmaceuticals and Wyeth partnered to develop an Aβvaccine for use in humans. The drug, named AN-1792,consisted of synthetic Aβ1−42 peptide in QS-21 adjuvant,and a phase I trial did not reveal significant adverse effectsin a limited cohort of 80 subjects. The phase IIa trial washalted prematurely, however, when four participants (∼5-6% of study subjects) developed clinical signs consistentwith aseptic meningoencephalitis [49]. Shortly after the trialwas halted, a case report was published of a 72-year-oldwoman who had a history of probable AD and had receivedAN-1792 and responded with elevated Aβ antibody titers.Upon histological examination, her brain showed extensiveareas of the neocortex with very few plaques and regionsdevoid of plaques that had punctate immunoreactivity forAβ that often colocalized with phagocytic microglia. Suchresults were consistent with previously published reports inAD transgenic mice suggesting that the vaccine instigatedmicroglial clearance of Aβ [50]. A subsequent study of eightparticipants who received immunization and developed Aβ-specific antibodies showed clear evidence of amyloid plaqueremoval but no effect of immunotherapy on preventionof cognitive decline [51]. Together, these data suggest thatpositive signal in mouse models of cerebral amyloidosis doesnot always translate to human AD and, in the case of Aβimmunotherapy, that careful preclinical toxicology in non-human primates is critically important.

4.2. Evidence from Mouse Genetics Approaches. Previousstudies have shown elevated CD45 expression on reactivemicroglia in AD brains compared with controls [52], andour group investigated the role of CD45 in responsiveness ofmicroglia to Aβ peptides [53]. Because CD45 is a membrane-bound protein-tyrosine phosphatase, we inhibited its func-tion in the context of Aβ stimulation by cotreating primarycultured microglia with a tyrosine phosphatase inhibitorand Aβ peptides. This resulted in secretion of TNF-α andnitric oxide that injured neurons in coculture conditions.Furthermore, treatment with an agonistic CD45 antibodymarkedly inhibited these detrimental effects via blockingp44/42 mitogen-activated protein kinase, suggesting thatCD45 activation promotes beneficial, neuroprotective func-tion of microglia. After stimulation with Aβ peptides,primary cultured microglia from CD45-deficient mice exhib-ited copious TNF-α release, nitric oxide production, andneuronal injury, and brains from Tg2576 mice deficientfor CD45 had significantly increased production of TNF-α compared with CD45-sufficient Tg2576 littermates. In


more recent studies, we reported that CD45-deficient PSAPPmice had increased abundance of soluble oligomeric andinsoluble Aβ (both extracellular and intracellular species),increased TNF-α and IL-1β proteins, and neuronal losscompared with CD45-sufficient PSAPP littermates [54].These studies demonstrate that the cell surface marker CD45promotes “good” microglial activation in the context of Aβchallenge, likely by endorsing an Aβ phagocytic phenotypethat mitigates cerebral amyloidosis.

There are also studies demonstrating that proinflamma-tory cytokines can promote beneficial neuroinflammationthat actually resolves cerebral amyloidosis in transgenicmice. In one of the earliest reports, Shaftel and colleaguesstudied the role of IL-1β in chronic neuroinflammationand in AD by engineering an IL-1βXAT transgenic mouse[55]. This model was constructed to overexpress IL-1β inthe CNS using the GFAP promoter. Following injectionof the FIV-Cre construct into hippocampi of these mice,a STOP codon in the IL-1βXAT transgene is excised, thusactivating overexpression of IL-1β in a temporal and spatialmanner. In this mouse model, IL-1β expression led torobust neuroinflammation characterized by activation ofastrocytes and microglia and induction of proinflammatorycytokines. Moreover, when IL-1βXAT mice were crossed withthe APP/PS1 mouse model of AD and the hippocampi of theresulting compound transgenic mice were injected with FIV-Cre, those authors observed dramatically reduced amyloidplaque pathology in the injected area of the brain. Addition-ally, Shaftel and colleagues showed that IL-1β overexpressioncaused an increase in the number of microglia overlappingwith amyloid plaques, an increase in Iba1 staining intensity,and high levels of MHC II expression in the same cells.These findings implicate IL-1β expression in activating a“good” form of neuroinflammation in APP/PS1 mice, whichthe authors suggested mediated enhanced phagocytosis ofamyloid plaques by activated microglia. However, theirstudies do not rule out the role that other cell types mighthave played in this scenario.

In another study, Chakrabarty and colleagues usedrecombinant adeno-associated virus serotype 1 (rAAV1) toexpress murine IFN-γ (mIFN-γ) in brains of the TgCRND8mouse model of cerebral amyloidosis. Those authors demon-strated the ability of this potent proinflammatory cytokine toclear amyloid plaques [56]. Specifically, neonatal TgCRND8mice injected with rAAV1-mIFN-γ in cerebral ventricleswere euthanized at 3 months of age for analysis. Theresults showed widespread increased immunoreactivity forboth GFAP and Iba1 in their brains. In addition, brainsof these mice exhibited decreased levels of soluble Aβ andAβ plaque burden, and did not show evidence of alteredAPP processing. Similar results were found after rAAV1-mIFN-γ injection into hippocampi at 4 months of age andpathological analysis 6 weeks later. Furthermore, mIFN-γexpression in vivo resulted in significant up-regulation ofseveral microglial markers (e.g., MHC I, MHC II, CD11b,and CD11c), suggesting a microglial phenotype reminiscentof an antigen-presenting cell. Chakrabarty and colleaguesalso demonstrated in in vitro studies that mouse microgliaprimed with mIFN-γ had increased uptake of fluorescently

tagged Aβ1−42 aggregates compared to control microglia.These results were not only restricted to mIFN-γ, as similarstudies from this group using IL-6 and TNF-α rAAVapproaches produced consistent findings [57, 58]. In contrastto the findings of Qiao et al. outlined in the previous section,DiCarlo and colleagues found that induction of multipleproinflammatory molecules following a single intrahip-pocampal injection of LPS into APP/PS1 transgenic miceresulted in activated microglia but reduced Aβ plaque loadcompared to saline-injected mice [59]. When taken together,these results suggest that certain forms of proinflammatorymicroglial activation are potentially beneficial for reducingAD-like pathology in transgenic mouse models.

In a different experimental paradigm, Wilcock andcolleagues deleted the microglial proinflammatory nitricoxide synthase 2 (NOS2) gene in the APPSwDI mouse modelof cerebrovascular amyloidosis. Those authors were ableto create a model with progressive amyloid pathology aswell as tau pathology and neuronal loss [60]. The authorspointed out that a difference in nitric oxide (NO) productionbetween human and mouse microglia may be a key factorin this result. As such, they hypothesized that lower levels ofNO production by human microglia create an environmentin which AD-like pathology is endorsed, whereas high levelsof NO (such as those produced by mouse microglia) areneuroprotective. Therefore, the authors suggest that NOS2deficiency creates a milieu that is conducive to AD pathology.This study provides yet another interesting example of howthe context of the brain inflammatory milieu can determinewhether microglia play a beneficial or detrimental role in theprogression of AD-like pathology. All of the studies reviewedsuggesting beneficial actions of microglia are summarized inTable 2.

5. Heterogeneous Microglial Activation States

As underscored by the studies reviewed above, it is becomingmore and more appreciated that microglial activation is notsimply a single phenotype. In fact, the most parsimoniousinterpretation of the evidence thus far points to broadheterogeneity of microglial activation states. But an openquestion remains as to how to best define these various formsof reactive microglia. On the one hand, an activation “contin-uum” likely exists that makes delimiting discrete phenotypesdifficult [61]. A complementary view is that microglia existin at least three distinct activated forms in the contextof neuroinflammatory diseases: classical (proinflammatory)activation, alternative (anti-inflammatory) activation, andacquired deactivation [62, 63]. In the context of mousemodels of cerebral amyloidosis, it is now clear that microgliaexhibit a mixed pattern of activation, with elements ofboth classical and alternative activation [62]. The picture isfurther complicated by different populations of microglialikely coexisting, each population with its own activatedphenotype. Clearly, one of the great challenges for thefield will be to define robust and informative markersthat predict functional outcomes of these heterogeneousmicroglial activation phenotypes.


Table 2: “Good” microglia in Alzheimer disease.

Publication(s) Type of study Observations

Martin et al., 2008 [41] EpidemiologicNo primary prevention of AD in an NSAID clinical trial; weakevidence for lower cognitive scores in naproxen users.

Schenk et al., 1999 [45] Mouse modelsAβ immunotherapy mitigates β-amyloid plaque pathology inPDAPP mice; phagocytic microglia colocalize with remainingAβ deposits.

Janus et al., 2000 [46];Morgan et al., 2000 [47]

Mouse modelsBehavioral impairment is reduced in Aβ-immunized TgCRND8or APP/PS1 transgenic mice.

Bard et al., 2000 [48] Mouse modelsPassive Aβ immunotherapy reduces cerebral amyloidosis inPDAPP mice. Remaining Aβ deposits colocalize with phagocyticmicroglia.

Nicoll et al., 2003 [50] NeuropathologicAN-1792 Aβ immunotherapy results in striking reduction ofamyloid pathology; remaining plaques colocalize withphagocytic microglia.

Tan et al., 2000 [53] Mouse modelsMicroglial CD45 negatively regulates microglial activation andopposes activated microglia-induced neuronal cell injury.

Zhu et al., 2011 [54] Mouse modelsMicroglial CD45 endorses phagocytosis and clearance of Aβpeptides and oligomers in PSAPP mice.

Shaftel et al., 2007 [55] Mouse modelsForcing brain IL-1β expression using IL-1βXAT transgenic miceactivates “good” neuroinflammation and dramatically reducesamyloid plaque pathology in APP/PS1 mice.

Chakrabarty et al., 2010[56]

Mouse modelsForcing cerebral IFN-γ expression leads to profoundneuroinflammation and clears amyloid plaques in TgCRND8mice via microglial phagocytosis.


Mouse modelsOverexpressing brain IL-6 leads to massive gliosis and clearsamyloid plaques in TgCRND8 mice via microglial phagocytosis.


Mouse modelsIncreasing cerebral proinflammatory TNF-α expression clearsamyloid pathology in TgCRND8 mice.

DiCarlo et al., 2001 [59] Mouse modelsAcute intrahippocampal injection of LPS reduces Aβ plaqueload in APP/PS1 transgenic mice.

Wilcock et al., 2008 [60] Mouse modelsAPPSwDI mice deficient in proinflammatory NOS2 have taupathology and neuronal loss.

6. But Do Brain-Resident MicrogliaPlay Any Role at All?

While many of the studies cited above suggest that microgliacan be deleterious or beneficial in the context of AD-like pathology depending on contextual cues, a recentstudy suggests that brain-resident microglia do not play asignificant role in the formation, maintenance or clearanceof amyloid plaques. Mathias Jucker and colleagues used aCD11b-tyrosine kinase/ganciclovir suicide gene approach tokill microglia for two to four weeks in two different ADmouse models (APP/PS1 and APP23) [64]. Selective ablationof microglia in APP/PS1 transgenic mice did not resultin differences in total Aβ burden, plaque morphology, ordistribution of cerebral Aβ deposits. While it is possible thatablation of brain-resident microglia for two to four weeksis not sufficient time to observe a significant change in Aβplaque remodeling in transgenic mouse models of cerebralamyloid deposition, this study implies that microglia arenot always primary players in the complex landscape of ADpathobiology.

7. Hematogenous Macrophages

As mentioned earlier, CNS-exogenous hematogenous ma-crophages have been suggested to play a role in the innateimmune responses in the brain. Independent studies fromthe laboratories of Mathias Jucker and Serge Rivest haveshown limited infiltration of peripheral mononuclear cellsinto the CNS of cerebral amyloidosis mouse models [65, 66].Both studies demonstrated that bone marrow-derived cellswere spatially associated with amyloid plaques. While Stalderand coworkers were not able to uncover evidence of amyloidphagocytosis within these cells by electron microscopy,Simard and colleagues presented convincing evidence ofamyloid deposits in GFP+ infiltrating mononuclear phago-cytes. Further, these authors crossed APP/PS1 mice withCD11b-tyrosine kinase mutant (TKmut30) transgenic mice inwhich proliferating CD11b+ cells can be specifically ablatedby administering the antiviral drug ganciclovir. Using thismouse model, the authors were able to convincingly showthat proliferating MHC II-positive peripheral mononuclearphagocytes played an important role in restricting β-amyloid


plaques. Another landmark study in this area was from thegroup of Joseph El Khoury. By crossing mice deficient inthe chemokine receptor Ccr2 with the Tg2576 mouse modelof cerebral amyloidosis, they were able to demonstrate thatrestriction of hematogenous microglia entry into the brainled to increased plaque load [67].

These observations led to studies by our group investigat-ing whether peripheral mononuclear phagocytes (hematoge-nous macrophages) could be targeted to infiltrate into thebrain and militate against AD-like pathology. We engineereda CD11c promoter-driven dominant-negative transforminggrowth factor-beta (TGF-β) type II receptor transgene inC57BL/6 mice (CD11c-DNR mice) [68], and were thus ableto genetically interrupt TGF-β and downstream Smad 2/3signaling specifically on peripheral innate immune cells. Wecrossed CD11c-DNR mice with the Tg2576 mouse modelof cerebral amyloid and evaluated behavioral impairmentand AD-like pathology [69]. Interestingly, doubly transgenicmice showed up to 90% attenuation of brain parenchymaland cerebrovascular amyloid deposits. Further, these ani-mals exhibited partial amelioration of cognitive impairmentand reduced astrocytosis, effects that were associated withincreased infiltration of Aβ-containing peripheral mononu-clear phagocytes in and around cerebral vessels and amyloidplaques. We were also able to observe Aβ immunoreactivitywithin the cytoplasm of these cells, suggesting that theseperipheral macrophages were actively clearing Aβ via phago-cytosis. In addition, the peripherally-derived macrophagesdisplayed an anti-inflammatory CD45+CD11b+Ly-6C− cellsurface phenotype and secreted elevated levels of the canon-ical anti-inflammatory cytokine, interleukin-10 [70, 71],suggesting that the beneficial effect of reduced β-amyloiddid not come at the cost of increased brain inflamma-tion. Additionally, we were able to demonstrate ∼3-foldincreased phagocytosis of Aβ by CD11c-DNR versus wild-type macrophages ex vivo and similar effects in vitro withpharmacologic inhibitors of TGF-β-Smad2/3 signaling, sug-gesting that inhibition of TGF-β-Smad 2/3 signaling allowsfor both peripheral mononuclear phagocyte recruitmentto brains of AD model mice and for phagocytic amyloidremoval.

8. Concluding Remarks

It is now becoming widely appreciated that there are nu-merous forms of “activated” microglia, some of which aredetrimental, and others, beneficial (Figure 1). In this paper,we have attempted to survey the state of the field with respectto both “good” and “bad” forms of reactive microgliosisin terms of AD-like pathology. A synthesis of the literatureonly seems possible when considering context—the condi-tions under which microglia encounter AD-like pathologicallesions. Specifically, a model emerges where microglia mountdifferent types of activated responses depending on whetherthey encounter particular species of misfolded protein (Aβor perhaps even tau) and whether this innate recognitionoccurs early on or after pathology is well-established. Whileit is not yet clear how microglial cells differentiate between

“Good’’ microglia “Bad’’ microglia

IL-6IL-1β

TNF-αTGF-βCx3cr1CD45

InflammationPhagocytosis↓

↑InflammationPhagocytosis

↓↑

CD40LCx3cr1

Cdk5/p25S100B

NO•

Figure 1: “Good” versus “Bad” microglia in Alzheimer disease.Illustration using 3D models of ramified “good” microglia andovoid “bad” microglia along with the array of immune moleculesthat likely help to determine which activated form of microgliawill respond to AD-like pathological lesions. It is postulated thatmicroglial phenotype can interconvert between ramified and ovoidfunctional states. The 3D images were generated using Imaris:Bitplane 3D modeling software and are provided courtesy of DavidGate.

these various forms of pathogenic peptides and proteins, it islikely that a varied set of immune molecules orchestrate thesecomplex innate immune responses. A deeper understandingof these molecules, and specifically, which pathways lead tobeneficial responses to clear pathogenic misfolded proteinsin AD, will be key for harnessing these innate immune cellsto militate against neuropathology.

Acknowledgments

T. Town is supported by the National Institute ofHealth/National Institute on Aging (5R00AG029726-04)and the National Institute of Health/National Instituteon Neurologic Disorders and Stroke (1R01NS076794-01), an Alzheimer’s Association Zenith Fellows Award(ZEN-10-174633), and an American Federation of AgingResearch/Ellison Medical Foundation Julie Martin Mid-Career Award in Aging Research (M11472). T. M. Weitzis supported by a National Institute of Health/NationalInstitute on Aging award (1R01NS076794-01). T. Town isthe inaugural holder of the Ben Winters Endowed Chair inRegenerative Medicine.

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